Novel Human-based Hepatic Safety Models for Mechanistic Risk Assessment: Deployment within the AstraZeneca hepatic safety toolbox

Abstract:

Drug-induced liver injury continues to be a major focus in candidate selection and clinical development in consideration of therapeutic index. Improved human cell based translational models, which recapitulate pathogenic mechanisms of liver toxicity, are required to assess hepatotoxicity risk to human.
An overview of hepatic adverse drug reaction and the pathogenesis and underlying mechanisms will be given. Pre-clinical hepatic safety questions that arise from projects and outline AstraZeneca’s hepatic safety assay toolbox will be discussed.
When and how AstraZeneca deploys particular assays for risk assessment vs hazard assessment will be described alongside assay validation and how we can move towards improved risk assessment through adoption of novel assays where we have confidence that correct hepatic safety mechanisms are appropriately represented.
Flow based Organs-Chip technology and 3D hepatic spheroid models represent promising models to assess mechanistic hepatotoxicity, due to enhanced cellular phenotype and stability whilst in culture. Evidence suggests these models demonstrate more in vivo-like injury mechanism representation and ability to report on drug-induced toxicity.
A comprehensive evaluation of an hepatic spheroid co-culture model and a Liver-Chip model will be outlined along with how this fits into an overall predictive model within AstraZeneca’s hepatic safety toolbox. Specifically, assessment of two model hepatotoxins for which metabolism is critical to their mechanisms of hepatotoxicity, acetaminophen (APAP) and
fialuridine (FIAU) have been assessed for sensitivity across a range of cytotoxicity biomarkers commonly employedin vitro(ATP, albumin, α-GST). Additionally, assessment of metabolic functionality by incorporating quantitation of APAP, FIAU and their principal metabolites has been evaluated.
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